Dose of radiation, survival, and side effects in intermediate-risk prostate cancer


There were a lot of data presented at the recent annual meeting of the American Society for Radiation Oncology (ASTRO) in San Francisco. Much of the data regarding prostate cancer was of relatively minor significance … but one paper seems to be of considerable importance.

According to a detailed report on the Medscape web site, the RTOG 0126 trial results may have thrown something of a spanner into the historical assumption that higher, accurate doses of radiation therapy would necessarily be more effective in the treatment of men with intermediate-risk prostate cancer.

RTOG 0126 was designed to compare the effectiveness and safety of higher-dose radiation therapy (with median doses of 79.2 Gy) to those of historically standard-dose radiation (with median doses of 70.2 Gy) in > 1,500 men who had all been diagnosed with intermediate-risk prostate cancer. However, after 10 years of follow-up, there was no evidence of a significant difference in overall survival between men in the high-dose group and men in the standard dose group — and these data are based on the largest study of radiation therapy in men with localized, intermediate-risk prostate cancer. What is more, long-term gastrointestinal and genitourinary toxicities were clearly more evident in men treated with the higher dose level.

The authors of the study apparently reported that:

  • The trial was conducted at 104 centers in North America.
  • The average (median) follow-up was 7.0 years for all patients and 7.6 years for survivors.
  • Patients all met standard criteria for intermediate-risk prostate cancer, which meant thaty had at least one of the following
    • A clinical stage of T2b disease and/or
    • A Gleason score of 7 and/or
    • A PSA level between 10 and 20 ng/ml
  • Prostate cancer-specific mortality was only 3 percent during the trial (accounting for just 13 percent of all deaths during the trial)
  • Most deaths occurred from other cancers (22 percent of patients) and from other causes (46 percent).
  • The actuarial 10-year overall survival rates were
    • 66.7 percent among men in the higher-dose group
    • 65.6 percent in the standard (lower) dose group
    • This difference was not statistically significant (hazard ratio [HR] = 0.98; P = 0.87).
  • Long-term (10-year) gastrointestinal toxicities of grade 2 or higher were observed in
    • 22 percent of patient treated with higher doses of radiation
    • 16 percent of patients treated with standard (lower) doses of radiation
  • Long-term (10-year) genitourinary toxicities of grade 2 or higher were observed in
    • 15 percent of patient treated with higher doses of radiation
    • 10 percent of patients treated with standard (lower) doses of radiation

However, there were significant and beneficial differences between the results of the patients in the two arms of the trial, as follows:

  • The actuarial 10-year biochemical failure rates (based on the ASTRO definition of biochemical failure) were
    • 30 percent in the higher-dose group
    • 45 percent in the standard (lower) dose group
    • This difference was statistically significant (HR = 0.42; P < 0.0001)
  • The actuarial 10-year biochemical failure rates (based on the Phoenix definition) were
    • 26 percent in the higher-dose group
    • 43 percent in the standard (lower) dose group
    • This difference is statistically significant (HR = 0.60; P < .0001).
  • The actuarial 10-year local progression rates were
    • 4 percent in the higher-dose group
    • 8 percent in the standard (lower) dose group
  • The actuarial 10-year rates of distant metastasis were
    • 5 percent in the higher-dose group
    • 8 percent in the standard (lower) dose group

So the bottom line to the study is that there were benefits to the higher-dose treatment in terms of risk for biochemical progression, risk for local progression, and risk for metastasis; there was no benefit in terms of of overall survival; and there was increased risk from the higher-dose in terms, most specifically, of long-term genitourinary and gastrointestinal side effects.

What are we to make of these data?

Dr. Patrick Song of Johns Hopkins, the commentator on these results at the ASTRO meeting, apparently made the following suggestions:

  • There are a number of characteristics that may indicate whether patients will be good candidates for lower-dose radiotherapy (70 to 72 Gy) as opposed to higher-dose treatment.
  • The intermediate-risk patients who seem to be less likely to benefit from high-dose radiation include  those patients who
    • Are older than 70 years
    • Have favorable-risk disease (with just one or perhaps two intermediate-risk factors)
    • Have < 50 percent of their biopsy cores positive for cancer
    • Have a PSA velocity of < 2 ng/ml per year
    • Have other clinically significant co-morbidities

It may be difficult to translate these data into practical clinical guidance that will be acceptable to some patients. There are a lot of data out there today that imply that a higher dose of radiation therapy is inevitably “better” in terms of curing prostate cancer. Indeed, other data presented at the ASTRO meeting confirmed this among high-risk patients. But “curing” prostate cancer is not necessarily the primary objective if such curative therapy makes no difference to overall survival and does significantly lower quality of life. The wise radiation oncologist (and the wise patient) will find ways to balance the known risks of high-dose treatment against the real need for that type of treatment based on the risk factors for the individual patient. One size is not going to fit all … and it never has.

14 Responses

  1. One obvious shortcoming of this study is that 10 years is not long enough to detect a significant prostate cancer mortality difference for men diagnosed at intermediate risk. The prostate cancer-specific mortality here was only 3%, and about two-thirds of the men were still alive after 10 years. Intermediate-risk men with > 10-year life expectancy may possibly enjoy a survival benefit from the higher dose.

    The definition of intermediate risk used in this study was: either

    (1) Stage T1b-T2b and Gleason score 2-6 and PSA 10-20 or
    (2) Stage T1b-T2b and Gleason score 7 and PSA < 15

    So the least favorable intermediate risk men, Gleason score 7 with T2c and PSA 15-20, were not included here. The definitions of intermediate risk have evolved — D'Amico did not include T2c, but NCCN does. Furthermore the distinction between Gleason 3 + 4 and GS 4 + 3 is increasingly emerging as an important one. Perhaps the authors will break out those Gleason scores separately on subsequent analysis if sample size permits. It may well turn out to be the case that the least favorable intermediate risk men may enjoy a survival benefit from higher dose. It may also be the case that this group may have a survival benefit from the addition of neoadjuvant + concurrent ADT, as Dr. D'Amico pointed out in his discussion at ASTRO of DART 01/05.

    For the most favorable intermediate-risk group, including those with Gleason ≤ 3 + 4, and especially with the features Dr. Song identified (older, low volume disease, favorable PSA kinetics, comorbidities), it may well turn out to be the case that even treatment with 70 Gy confers no survival advantage over expectant management.

    As a secondary analysis, the authors (http://www.redjournal.org/article/S0360-3016(13)02953-2/abstract) also looked at treatment using IMRT vs 3D-CRT. They found that late rectal toxicity was reduced by the use of IMRT. Zelefsky, in a commentary (http://www.redjournal.org/article/S0360-3016(13)03091-5/fulltext), points out that rectal dose may be reduced by a number of methods, and late urinary toxicity may be reduced in the future as well, obviating the need to reduce dose. Unfortunately, sexual adverse effects are not mentioned anywhere.

  2. You have shared data showing a much higher risk of a secondary cancer (bladder and rectum) in men treated with external beam radiation. Did this study note any of these cancers over the long period of follow-up?

  3. Dear Allen:

    Exactly what the authors of this study meant by “intermediate risk” is actually very poorly explained in the abstract. Strictly speaking, a man is at intermediate risk if he has clinical stage T2b disease and/or Gleason 7 and/or a PSA anywhere between 10 and 20 ng/ml. In addition, the formal use of T2c as a clinical stage in prostate cancer was abandoned some time ago. The proper staging for prostate cancer today is T2a if the cancer is in one lobe of the prostate and T2b if it is in both lobes. This only adds to the confusion, because patients in this paper were probably being diagnosed when T2c was still an accepted stage for prostate cancer and implied cancer in both lobes of the prostate. However, what I am quite sure of was that the definition of intermediate-risk used in this study was not as simple as either (1) or (2) as you state them above.

    Most of the analysis is speculative by comparison with the statistically significant data. Note that the reason that the trial was stopped was because it had become statistically futile to expect to see the originally hoped-for overall survival benefit of 23% between the two arms, despite the small number of prostate cancer-specific deaths, because the number of deaths from all causes was too high. Thus even if the trial had been followed until all the patients had died, any overall survival benefit was going to be minimal.

  4. Dear Bob:

    I have only seen the abstract of this paper, not the full text, so I have no answer to your question. There is no reference to other specific cancers in the abstract.

  5. When was cT2c abandoned? It is still part of the AJCC 7th edition, which I believe is the most current.

    I didn’t make up those definitions. They are what was presented at the ASTRO meeting. You can watch the presentation for yourself. Skip to time 43:00-51:00.

  6. Allen:

    The AJCC 7th edition was last updated in 2000 and is widely recognized as being somewhat outdated. The 8th edition is expected in 2015. However the global urology community (through the UICC) formally abandoned the use of cT2c back in 1997 on the basis of recommendations from people like Dr. Epstein and other members of the specialized urologic pathology community because any significant distinction between the original cT2a and cT2b (one or both halves of one lobe) was actually impossible to determine with any real degree of accuracy unless one was looking at a pathologic specimen. The AJCC accepted that change in 1997 but then (for reasons unknown to me) reinstated the cT2c stage in their 2000 edition, even though the global urology community still doesn’t formally accept that (as far as I am aware).

    I’ll have a look at the video. Thank you for the link, although those two definitions of intermediate risk make no sense to me whatsoever. They may reflect poorly written slides (which can occur frequently in initial presentations like this that don’t get proof-read prior to presentations).

  7. I believe you may be mistaken about the staging change. Do you have a reference? My urologist still uses cT2c for felt or imaging-detected cancer in both lobes. If he feels a small lump on one side, it’s cT2a; if it’s lumpy throughout that side, it’s cT2b. Since he uses mpMRIs, he also uses that for staging. The AJCC 7th edition was released in 2010, not 2000. You can see the release history here.

    The slides were not incorrect. The patient population for the RTOG 0126 protocol is clearly laid out here.

    I should add that stages T2b and T2c are still part of the most recent version (2.2014) of the NCCN prostate cancer physician guidelines in their definition of “intermediate risk.”

  8. PREMATURE RESULTS FOR OVERALL SURVIVAL

    I’ll join Allen’s chorus in believing that median follow-ups of 7.0 years for non-survivors and 7.6 years for survivors are way to short in view of follow-up treatment options available today, first conventional sophisticated ADT and secondary ADT, but also the new drugs for late-stage disease, to say nothing of chemo options.

    The current American Cancer Society statistics for survival from diagnosis for all stages of prostate cancer are:

    — The relative 5-year survival rate is almost 100%
    — The relative 10-year survival rate is 99%
    — The 15-year relative survival rate is 94%

    Looking at what the ACS refers to as stage, it is clear that most of the lethality comes in the group with distant metastases, which is unlikely to be significantly represented in this study’s population:

    — Local disease — nearly 100% relative survival at 5 years
    — Regional disease — nearly 100% relative survival at 5 years
    — Distant disease — 28% relative survival at 5 years

    (Source: http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates)

    However, the paper does underscore that a number of considerations should come into play when selecting a treatment, such as age and co-morbidities, to select just two.

  9. Dear Allen:

    I know I am not “mistaken” about the staging change. What I think we are dealing with here is a difference in the opinions of different organizations. If you look at the Kattan nomogram for prediction of outcomes after a radical prostatectomy on the MSKCC web site, there is a very clear distinction between the data you are asked to provide about clinical stage prior to and after 1997 based on the UICC staging system. Prior to 1997, T2c was an option; after 1997 it is was not an option. Peter Scardino and the MSKCC are not exactly lightweights.

    The only way that I can see to get any clarity about this would be to talk to a urologist who was a participant in all of the relevant discussions. I do know that for an extended period of time the staging information about prostate cancer on the NCI web site absolutely did not include any reference to cT2c, and now it does again. Why is beyond me because there is extensive information pointing out that the differences between whether there is cancer in one or both halves of a single lobe is of minimal clinical significance, whereas there is some clinical significance to the presence of cancer in only one lobe as opposed to both lobes.

  10. The data used to build that nomogram was based on patients diagnosed between 1983-2002, many of whom were diagnosed pre-PSA screening. They used staging data from the 1992 staging protocol and the 1997 staging protocols because that was the data they had back then for those men. It doesn’t mean that current staging protocols are controversial or questionable, it was just that that was what was known and available back then. By 2002, they had changed the staging groups back to include cT2a, b, and c, and it has stayed that way since. BTW, that was also the year they included the PSA groups and the Gleason scores (rather than grades) in their risk stratification. I assume it changed based on updated risk stratification, and improved imaging.

    Far from being of “minimal clinical significance,” there is an important distinction between cT2a, which can be part of “low risk” disease (if GS = 6 and PSA < 10) and cT2b, which is always an indicator of at least intermediate-risk disease. If the index tumor theory is correct, the distinction between one small lump and a whole lumpy lobe is indeed important. The important thing to remember about staging, is that it is based on clinically apparent disease rather than microfoci. However, as CDUS and mpMRI become more prevalent, that distinction may eventually disappear.

    One can argue that the current staging and risk stratification should be changed to include more precise categories (e.g., T3a1 for focal ECE, favorable/unfavorable intermediate risk) or larger groupings (e.g., favorable risk/unfavorable risk), but that is a big topic I'll leave for another day.

    Jim, Thanks for that data. It reminds us of the importance of using surrogate endpoints when evaluating the effectiveness of interventions on diseases that have such long natural histories as newly diagnosed intermediate risk disease. There will never be the money or the sample size for long enough follow-up, and even if there were, the interventions become outmoded and the findings irrelevant over that long a time span.

  11. Dear Allen:

    And now I need to know if you have a reference for UICC or anyone else changing staging data back to include cT2c in 2002, because I know for absolute certain that in 2010 at the every earliest the published NCI staging data on prostate cancer still did not include cT2c. The “They” that you are referring to as changing back to cT2c is the NCCN, but they are not actually the authoritative body at all, and there is clearly confusion among urologists — many of whom will no longer give a clinical T-stage that is any more refined than T2.

    Frankly I can see no justification for refining the clinical staging process to include anything like cT3a1, etc., because the available clinical data are rarely accurate enough to allow for such refinement — even when one includes data from things like MRI scans and color Doppler ultrasound. One can certainly refine the pathological stage (if you are a sufficiently skilled pathologist), but the fact is that most pathologists are not sufficiently skilled.

    I am utterly unable to find any published justification for the return to the use of cT2c. Can you?

  12. The “they” I was referring to as changing the staging in 2002 was the AJCC, not NCCN. I think their TNM staging system is universally used in the US, and the UICC follows their lead internationally. For the reference, click here; on page 310, it says:

    “Since publication of the Fifth Edition of the AJCC Cancer Staging Manual, review of the results of clinical series of patients with T2 tumors has demonstrated that recurrence-free survival following treatment was statistically different if the Fourth Edition system of T2a, T2b and T2c stratification was used. Therefore, to enhance the characterization of palpable tumors, the Sixth Edition has reincorporated the three clinical stages T2a (palpable tumor confined to less than one-half of one lobe), T2b (palpable tumor involving more than half of one lobe, but not both lobes), and T2c (tumor involving both lobes).”

    I haven’t heard any confusion about this staging among urologists that I have met, or whose studies I’ve read. There are, however, various risk stratification systems (e.g., AJCC, CAPRA, D’Amico and NCCN) that differ on which stage is assigned to each risk category. Aside from PSA group, GS and other risk indicators, D’Amico assigns only T2b to intermediate risk and T2c to high risk; NCCN assigns both T2b and T2c to intermediate risk; CAPRA gives all T1 and T2 a zero score (lower risk); AJCC puts T2b in prognostic group IIA, and T2c in group IIB. I’m sure that risk stratification will continue to evolve.

  13. Allen:

    THANK you … That is very helpful indeed, and I will need to make some changes to other baseline documents on the site as a consequence.

    I shall also see if I can find the source material for this decision because it doesn’t seem to correlate with other information.

    :O)

  14. Glad to see Allen’s comment about T2c. I do remember the reincorporation of the T2c primary tumor descriptor in the AJCC 6th edition, and at the time regarded it as a bit of oncologic trivia. It does make sense, though: in prostate cancer (and most others), more disease is worse.

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